dbSNP rs7698598: SYNPO2:p.Thr573Ala (chr4-119030492-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_133477.3(SYNPO2):c.1717A>G(p.Thr573Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.859 in 1,613,934 control chromosomes in the GnomAD database, including 596,283 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.85 ( 55271 hom., cov: 30)

Exomes 𝑓: 0.86 ( 541012 hom. )

Consequence

SYNPO2
NM_133477.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.488

Publications

37 publications found

Variant links:

Genes affected

SYNPO2 (HGNC:17732): (synaptopodin 2) Enables alpha-actinin binding activity and filamin binding activity. Involved in positive regulation of actin filament bundle assembly; positive regulation of cell migration; and regulation of Rho-dependent protein serine/threonine kinase activity. Located in several cellular components, including Z disc; focal adhesion; and stress fiber. [provided by Alliance of Genome Resources, Apr 2022]

SYNPO2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.2677783E-7).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.878 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNPO2	NM_133477.3 link	c.1717A>G	p.Thr573Ala	missense_variant	Exon 4 of 5	ENST00000307142.9	NP_597734.2	Q9UMS6-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNPO2	ENST00000307142.9 link	c.1717A>G	p.Thr573Ala	missense_variant	Exon 4 of 5	1	NM_133477.3	ENSP00000306015.4		Q9UMS6-2

Frequencies

GnomAD3 genomes

AF:

0.852

AC:

129464

AN:

151940

Hom.:

55223

Cov.:

show subpopulations

Gnomad AFR

AF:

0.822

Gnomad AMI

AF:

0.898

Gnomad AMR

AF:

0.890

Gnomad ASJ

AF:

0.879

Gnomad EAS

AF:

0.869

Gnomad SAS

AF:

0.808

Gnomad FIN

AF:

0.805

Gnomad MID

AF:

0.934

Gnomad NFE

AF:

0.868

Gnomad OTH

AF:

0.877

GnomAD2 exomes

AF:

0.853

AC:

214250

AN:

251162

AF XY:

0.851

show subpopulations

Gnomad AFR exome

AF:

0.818

Gnomad AMR exome

AF:

0.871

Gnomad ASJ exome

AF:

0.886

Gnomad EAS exome

AF:

0.878

Gnomad FIN exome

AF:

0.816

Gnomad NFE exome

AF:

0.866

Gnomad OTH exome

AF:

0.863

GnomAD4 exome

AF:

0.860

AC:

1256920

AN:

1461876

Hom.:

541012

Cov.:

AF XY:

0.858

AC XY:

623903

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.822

AC:

27515

AN:

33480

American (AMR)

AF:

0.874

AC:

39094

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.886

AC:

23164

AN:

26136

East Asian (EAS)

AF:

0.847

AC:

33636

AN:

39700

South Asian (SAS)

AF:

0.798

AC:

68795

AN:

86258

European-Finnish (FIN)

AF:

0.818

AC:

43709

AN:

53414

Middle Eastern (MID)

AF:

0.869

AC:

5014

AN:

5768

European-Non Finnish (NFE)

AF:

0.867

AC:

963665

AN:

1112000

Other (OTH)

AF:

0.866

AC:

52328

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

12727

25453

38180

50906

63633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21278

42556

63834

85112

106390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.852

AC:

129573

AN:

152058

Hom.:

55271

Cov.:

AF XY:

0.850

AC XY:

63177

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.822

AC:

34084

AN:

41476

American (AMR)

AF:

0.891

AC:

13604

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.879

AC:

3053

AN:

3472

East Asian (EAS)

AF:

0.868

AC:

4469

AN:

5146

South Asian (SAS)

AF:

0.808

AC:

3892

AN:

4814

European-Finnish (FIN)

AF:

0.805

AC:

8513

AN:

10574

Middle Eastern (MID)

AF:

0.929

AC:

273

AN:

294

European-Non Finnish (NFE)

AF:

0.868

AC:

59012

AN:

67982

Other (OTH)

AF:

0.878

AC:

1854

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

971

1941

2912

3882

4853

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

892

1784

2676

3568

4460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.867

Hom.:

232034

Bravo

AF:

0.859

TwinsUK

AF:

0.860

AC:

3190

ALSPAC

AF:

0.869

AC:

3348

ESP6500AA

AF:

0.820

AC:

3614

ESP6500EA

AF:

0.870

AC:

7478

ExAC

AF:

0.848

AC:

103006

Asia WGS

AF:

0.865

AC:

3011

AN:

3478

EpiCase

AF:

0.877

EpiControl

AF:

0.871

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.76

(source)

DANN

Benign

0.13

DEOGEN2

Benign

0.0052

.;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.027

T;T;T;T

MetaRNN

Benign

9.3e-7

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

.;N;N;N

PhyloP100

0.49

PrimateAI

Benign

0.23

PROVEAN

Benign

0.37

.;N;N;N

REVEL

Benign

0.068

Sift

Benign

1.0

.;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.022

MPC

0.076

ClinPred

0.0034

GERP RS

1.9

Varity_R

0.032

gMVP

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over